Process for the preparation of amides from hindered anilines containing a perhaloalkyl group

ABSTRACT

The present invention provides a novel and improved process for the production of the production of hindered anilines containing perfluoroalky groups in good yield any by using close to stoichiometric amounts of acylating agent.

Hindered anilines containing perhaloalkyl groups are known to have low reactivity towards acylating agents. Standard methods of acylation such as treatment with acid chloride or anhydride in the presence of base and a nucleophilic catalyst proceed only in low yields, the major side reaction being double acylation. It is possible to obtain these amides in modest yield by using two equivalents of acylating agent followed by hydrolytic cleavage of one acyl group. However this method involves sacrificing at least one equivalent of often valuable acylating partner (see for example WO2008000438 and WO2010127928).

It is clear that a significant disadvantage of the prior art process is the sacrificial use of an excess acylating agent, which makes this process uneconomical and especially unsuitable for a large-scale production.

A method for enhancing the reactivity has now surprisingly been found that allows the preparation of the desired amides in good yield and by using close to stoichiometric amounts of acylating agent.

The aim of the present invention relates therefore to provide a novel and improved process for the acylation of hindered anilines containing perhaloalkyl groups.

Therefore the present invention relates to a process for the preparation of compounds of formula VI

comprising at least the following steps a) to c):

Step a)

-   -   reacting a compound of formula (I) with a compound of         formula (II) to obtain a compound of formula (III):

then

Step b)

-   -   reacting the compound of formula (III) with a compound of         formula (IV) to obtain a compound of formula (V):

then

Step c)

-   -   reacting the compound of formula (V) with aqueous base to obtain         a compound of formula (VI):

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl;

R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl;

R₂ is H or C₁-C₄-alkyl;

R₃ is H, fluorine, methoxy;

R_(3a) is H or CN,

Q₁ is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl;

R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl;

R₂ is H or C₁-C₄-alkyl;

R₃ is H, fluorine, methoxy;

R_(3a) is H or CN,

Q₁ is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that R₃ is H when R_(3a) is CN, and that R₃ is fluorine or methoxy when R_(3a) is H;

More preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl;

R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl;

R₂ is H or C₁-C₄-alkyl;

R₃ is H, fluorine, methoxy;

R_(3a) is H or CN,

Q₁ is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R_(3a) are H;

and provided that R₃ is H when R_(3a) is CN, and that R₃ is fluorine or methoxy when R_(3a) is H;

The above reaction steps are described in more detail below.

The present invention further relates to compounds according to formula (III)

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio;

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl;

The present invention further relates to compounds according to formula (IV)

wherein X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl;

R₂ is C₁-C₄-alkyl;

R₃ is H, fluorine or methoxy;

R_(3a) is H or CN;

Q₁ is 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R_(3a) are H;

Preferably in the compounds according to formula (IV) X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl;

R₂ is C₁-C₄-alkyl;

R₃ is H, fluorine or methoxy;

R_(3a) is H or CN;

Q₁ is 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

provided that not both R₃ and R_(3a) are H;

and provided that R₃ is H when R_(3a) is CN, and that R₃ is fluorine or methoxy when R_(3a) is H;

The present invention further relates to compounds according to formula (V)

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio,

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl;

R₂ is H or C₁-C₄-alkyl;

R₃ is H, fluorine, methoxy;

R_(3a) is H or CN,

provided that R₃ is H when R_(3a) is CN;

Q₁ is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

The compounds according to the invention, namely the compounds of formula (III), (IV) and (V), and the compounds mentioned in the method according to the invention may exist in different geometric or optical isomers or tautomeric forms.

This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

The invention also covers salts of all compounds of the invention.

In particularly preferred embodiments for the methods and compounds of the invention (namely the compounds of formula (III), (IV) and (V)) and the compounds mentioned in the method according to the invention, the preferred groups for X₁, X₂, X₃, X₄, R₁, R₂, R₃, R_(3a) and Q₁ in any combination thereof, are as set out below.

In one preferred embodiment R₃ is H, fluorine or methoxy

In one preferred embodiment R₃ is H;

In another preferred embodiment R₃ is fluorine;

In still another preferred embodiment R₃ is methoxy.

In one preferred embodiment R_(3a) is H or cyano

In one preferred embodiment R_(3a) is H;

In another preferred embodiment R_(3a) is cyano;

In one preferred embodiment R₃ is H and R_(3a) is H

In one preferred embodiment R₃ is fluorine and R_(3a) is H

In one preferred embodiment R₃ is methoxy and R_(3a) is H

In one preferred embodiment R₃ is H and R_(3a) is CN

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H, C₁-C₄ alkyl;

More preferred R₁ is H, methyl;

Most preferred R₁ is methyl.

Preferably R₂ is H, methyl or ethyl;

More preferred R₂ is H or ethyl.

Preferably Q₁ is 4-cyano-phenyl, 2-methyl-4-cyano-phenyl or 4-pyridyl;

In a more preferred embodiment Q₁ is 2-methyl-4-cyano-phenyl or 4-pyridyl;

In a further more preferred embodiment Q₁ is 4-cyano-phenyl;

In an even more preferred embodiment Q₁ is 4-pyridyl;

In a further even more preferred embodiment Q₁ is 2-methyl-4-cyano-phenyl.

In one preferred embodiment (A) R₃ is H, fluorine or methoxy and R_(3a) is H;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferrably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H or C₁-C₄ alkyl;

More preferred R₁ is H or methyl;

Most preferred R₁ is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Q₁ is 4-cyano-phenyl or 4-pyridyl;

Further preferred Q₁ is 4-pyridyl;

Further preferred Q₁ is 4-cyano-phenyl

Further preferred Q₁ is 3-pyridyl or 4-pyridyl.

In one preferred embodiment (B) R₃ is H and R_(3a) is H;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl ordifluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H or C₁-C₄ alkyl;

More preferred R₁ is H or methyl;

Most preferred R₁ is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Q₁ is 4-cyano-phenyl or 4-pyridyl;

Further preferred Q₁ is 4-pyridyl;

Further preferred Q₁ is 4-cyano-phenyl

Further preferred Q₁ is 3-pyridyl or 4-pyridyl;

In one preferred embodiment (C) R₃ is fluorine and R_(3a) is H;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl ordifluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H or C₁-C₄ alkyl;

More preferred R₁ is H or methyl;

Most preferred R₁ is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Q₁ is 4-cyano-phenyl or 4-pyridyl;

Further preferred Q₁ is 4-pyridyl;

Further preferred Q₁ is 4-cyano-phenyl;

Further preferred Q₁ is 3-pyridyl or 4-pyridyl;

In one preferred embodiment (D) R₃ is methoxy and R_(3a) is H;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferrably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H or C₁-C₄ alkyl;

More preferred R₁ is H or methyl;

Most preferred R₁ is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Q₁ is 4-cyano-phenyl or 4-pyridyl;

Further preferred Q₁ is 4-pyridyl;

Further preferred Q₁ is 4-cyano-phenyl

Further preferred Q₁ is 3-pyridyl or 4-pyridyl;

In one preferred embodiment (E) R₃ is H and R_(3a) is cyano;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or C₁-C₄ alkoxymethyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ haloalkoxy;

Most preferred X₁ and X₂ each independently are halogen, methyl, ethyl, trifluoromethyl or difluoromethoxy.

Preferably X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

More preferred X₃ are heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Even more preferred X₃ are heptafluoroprop-2-yl or 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl.

Preferrably X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

More preferred X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

Even more preferred X₄ is a leaving group selected from halogen;

Most preferred X₄ is a chloride.

Preferably R₁ is H or C₁-C₄ alkyl;

More preferred R₁ is H or methyl;

Most preferred R₁ is methyl.

Preferably R₂ is methyl or ethyl;

More preferred R₂ is ethyl.

Preferably Q₁ is 4-cyano-phenyl or 4-pyridyl;

Further preferred Q₁ is 4-pyridyl;

Further preferred Q₁ is 4-cyano-phenyl

Further preferred Q₁ is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (A) Q₁ is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (A) Q₁ is 4-pyridyl;

In a further preferred embodiment (A) Q₁ is 4-cyano-phenyl;

In a further preferred embodiment (a) Q₁ is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (B) Q₁ is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (B) Q₁ is 4-pyridyl;

In a further preferred embodiment (B) Q₁ is 4-cyano-phenyl;

In a further preferred embodiment (B) Q₁ is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (C) Q₁ is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (C) Q₁ is 4-pyridyl;

In a further preferred embodiment (C) Q₁ is 4-cyano-phenyl;

In a further preferred embodiment (C) Q₁ is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (D) Q₁ is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (D) Q₁ is 4-pyridyl;

In a further preferred embodiment (D) Q₁ is 4-cyano-phenyl;

In a further preferred embodiment (D) Q₁ is 3-pyridyl or 4-pyridyl;

In a preferred embodiment (E) Q₁ is 4-cyano-phenyl or 4-pyridyl;

In a further preferred embodiment (E) Q₁ is 4-pyridyl;

In a further preferred embodiment (E) Q₁ is 4-cyano-phenyl;

In a further preferred embodiment (E) Q₁ is 3-pyridyl or 4-pyridyl;

Preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy or C₁-C₄ alkoxymethyl;

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

R₁ is H or C₁-C₄ alkyl;

R₂ is methyl or ethyl;

Q₁ is 2-pyridyl or 4-pyridyl.

Equally preferably X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl,

X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—;

R₁ is H, C₁-C₄ alkyl,

R₂ is methyl or ethyl

Q₁ is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy;

X₃ is heptafluoroprop-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

R₁ is H or methyl;

R₂ is ethyl;

Q₁ is 4-pyridyl.

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,

X₃ is 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

R₁ is H, methyl,

R₂ is ethyl

Q₁ is 4-pyridyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,

X₃ is 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

R₁ is H, methyl,

R₂ is ethyl

Q₁ is 4-pyridyl;

More preferred X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,

X₃ is nonafluorobut-2-yl;

X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—;

R₁ is H, methyl,

R₂ is ethyl

Q₁ is 4-pyridyl;

More preferred R₃ is methoxy; and R_(3a) is H,

More preferred R₃ is fluorine; and R_(3a) is H,

More preferred R₃ is H; and R_(3a) is CN,

More preferred R₃ is H; R_(3a) is H,

The following schemes describe the reactions of the invention in more detail. The substituent definitions are the same as defined previously:

Step a)

Compounds of formula (III) can be prepared by reacting compounds of formula (I) with compounds of formula (II).

The reactions of compounds of formula (I) with compounds of formula (II) are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to carbonates such as Na₂CO₃, K₂CO₃, hydroxides such as NaOH, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine. The reactions of compounds of formula (I) with compounds of formula (II) are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents such as toluene, chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, THF, dioxane, preferably chloroform, dichloromethane. It is also possible to conduct the reaction in a biphasic mixture of an organic solvent and water. The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C. (e.g. greater than −20° C., preferably greater than 0° C., e.g. lower than 100° C., preferably lower than 30° C.).

The reactions of compounds of formula (I) and (II) are preferably carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts capable of promoting acyl transfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles, phosphines, imidazolylidene carbenes, 1,2-diamines, bicyclic amidines, isothioureas and guanidines, triazoles, some alcohols, iodide and cyanide salts, preferably 4-dimethylaminopyridine.

Alternatively the reaction can be carried out in the presence of a catalytic amount of a suitable acid. Suitable acids include but are not limited to mineral acids such as sulfuric acid, hydrochloric acid and organic acids such as trifluoroacetic acid.

The reactions of compounds of (I) and (II) are carried out either by using compound of formula (II) as the solvent or in the presence of suitable additional organic solvent. Suitable solvents include but are not limited to dichloromethane, dichloroethane, THF and dioxane.

The reaction can be carried out at a temperature from 0° C. to 120° C., preferably from 30° C. to 100° C. (e.g. greater than 0° C., preferably greater than 30° C., e.g. lower than 120° C., preferably lower than 70° C.).

The reaction between compounds of formula (I) and compounds of formula (II) can be carried out under acidic conditions to yield compounds of formula III. Compounds of formula III can be formed by hydrolysis of intermediate compounds of formula IIIa. It is thus preferable to treat the resulting mixture of compounds of formula (III) and diacylated intermediate (IIIa) obtained in step a, with a suitable aqueous base. Suitable bases include, but are not limited to, aqueous solutions of NaOH, LiOH, Na₂CO₃, or K₂CO₃. Suitable organic co-solvents include, but are not limited to, THF and dioxane.

Step b)

Compounds of formula (V) can be prepared by reacting compounds of formula (III) with compounds of formula (IV).

The reactions of compounds of formula (III) with compounds of formula (IV) are preferably carried out in the presence of a suitable base. Suitable bases include, but are not limited to, carbonates such as Na₂CO₃, K₂CO₃, hydroxides such as NaOH, nitrogen-based organic bases such as amines, pyridines and derivatives thereof, e.g. triethylamine, tri-n-propylamine, pyridine and diisopropylethylamine. The reactions of compounds of formula (III) with compounds of formula (IV) are preferably carried out in the presence of a solvent. Suitable solvents include, but are not limited to organic solvents such as toluene, chloroform, dichloromethane, dichloroethane, monochlorobenzene, dichlorobenzene, trichlorobenzene, 4-fluorotoluene, THF, or dioxane, preferably chloroform ordichloromethane. It is also possible to conduct the reaction in a biphasic mixture of an organic solvent and water. The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C. (e.g. greater than −20° C., preferably greater than 0° C., e.g. lower than 100° C., preferably lower than 30° C.).

The reactions of compounds of formula (III) and (IV) could be carried out in the presence of a catalyst. Suitable catalysts include, but are not limited to nucleophilic catalysts capable of promoting acyl transfer reactions such as 4-dialkylaminopyridines, N-alkylimidazoles, phosphines, imidazolylidene carbenes, 1,2-diamines, bicyclic amidines, isothioureas and guanidines, triazoles, some alcohols, iodide and cyanide salts, preferably 4-dimethylaminopyridine.

Step c)

Compounds of formula (VI) can be prepared by reacting compounds of formula (V) with a suitable base. Suitable bases include but are not limited to aqueous solutions of NaOH, LiOH or K₂CO₃. The reactions of compounds of formula (VI) with an aqueous base are preferably carried out in the presence of a suitable organic co-solvent. Suitable solvents include, but are not limited to, THF, dioxane and ethanol.

The reaction can be carried out at a temperature from −20° C. to 100° C., preferably from 0° C. to 30° C. (e.g. greater than −20° C., preferably greater than 0° C., e.g. lower than 100° C., preferably lower than 30° C.).

Alternatively the compounds of formula (VI) can be prepared in a one pot process by reacting compounds of formula (III) with compounds of formula (IV) as described for step b, followed by addition of a suitable aqueous base.

Suitable bases include, but are not limited to LiOH, NaOH, KOH, Na₂CO₃, K₂CO₃.

1) Acid halides of formula (IV), wherein R is Cl, F or Br, may be made from carboxylic acids of formula (IV), wherein R is OH by treatment with thionyl chloride, oxalyl chloride or phosgene.

2) Carboxylic acids of formula (IV), wherein R is OH, may be formed from esters of formula (IV), wherein R is C₁-C₆alkoxy by treatment of the ester with an alkali hydroxide, such as lithium hydroxide, in a solvent, such as a mixture of THF and water.

3) Esters of formula (IV), wherein R is C₁-C₆alkoxy, may be made by reacting compounds of formula (VII), wherein R is C₁-C₆alkoxy, by acylation with a carboxylic acid of formula (VIII) wherein R₄ is OH or with acid halide of formula (VIII) wherein R₄ is Cl, F or Br. When R₄ is OH such reactions may be carried out in the presence of a coupling reagent, such as DCC (N,N′-dicyclohexyl-carbodiimide), EDC (1-ethyl-3-[3-dimethylamino-propyl]carbodiimide hydrochloride) or BOP-Cl (bis(2-oxo-3-oxazolidinyl)phosphonic chloride), in the presence of a base, such as pyridine, triethylamine, 4-(dimethylamino)pyridine or diisopropylethylamine, and optionally in the presence of a nucleophilic catalyst, such as hydroxybenzotriazole. When R₄ is Cl, such reactions may be carried out under basic conditions, for example in the presence of pyridine, triethylamine, 4-(dimethylamino)pyridine or diisopropylethylamine, and optionally in the presence of a nucleophilic catalyst. Alternatively, the reaction may be conducted in a biphasic system comprising an organic solvent, preferably ethyl acetate, and an aqueous solvent, preferably a solution of sodium bicarbonate. When R₄ is C₁-C₆alkoxy the ester may be converted directly to the amide by heating the ester and amine together in a thermal process.

4) Compounds of formula (VII), wherein R is C₁-C₆alkoxy, may be made from compounds of formula (IX) by sequential treatment with an alcohol R—OH under acidic conditions and then formation of the N—R¹ bond. For example, reductive amination may be achieved by treatment of the amine with an aldehyde or ketone and a reducing agent such as sodium cyanoborohydride. Alternatively, alkylation may be achieved by treating the amine with an alkylating agent such as an alkyl halide, optionally in the presence of a base.

6) Alternatively, compounds of formula (VII), wherein R is C₁-C₆alkoxy, may be made from a compound of formula (X), wherein R is C₁-C₆alkoxy and LG is a leaving group, such as fluoro, chloro or sulfonate, via the displacement of the leaving group by an amine of formula R¹—NH₂ or other imine analogue followed by hydrolysis with a metal catalyst. See, for example: Chemical Communications (2009), (14), 1891-1893 or Journal of Organic Chemistry (2000), 65(8), 2612-2614.

Compounds of formula (X) and amines of formula R¹—NH₂ are either known compounds or may be made by methods known to a person skilled in the art.

6a) Alternatively, compounds of formula (VII), wherein R is C₁-C₆alkoxy, may be made from a compounds of formula (XI), wherein R is C₁-C₆alkoxy via reduction in the presence of a metal catalyst and a suitable two carbon building block such as acetaldehyde or acetonitrile. See for example: J. Org. Chem. 2007, 72, 9815 or Org. Lett. 2005, 7, 471

The following Examples illustrate, but do not limit, the invention.

TABLE A (V)

Line n° X₃ R₁ R₂ R₃ R_(3a) Q₁ A.1 heptafluoroprop-2-yl H Me H H 3-Pyridyl A.2 nonafluorobut-2-yl H Me H H 3-Pyridyl A.3 heptafluoroprop-2-yl Me Me H H 3-Pyridyl A.4 nonafluorobut-2-yl Me Me H H 3-Pyridyl A.5 heptafluoroprop-2-yl H Et H H 3-Pyridyl A.6 nonafluorobut-2-yl H Et H H 3-Pyridyl A.7 heptafluoroprop-2-yl Me Et H H 3-Pyridyl A.8 nonafluorobut-2-yl Me Et H H 3-Pyridyl A.9 heptafluoroprop-2-yl H Me F H 3-Pyridyl A.10 nonafluorobut-2-yl H Me F H 3-Pyridyl A.11 heptafluoroprop-2-yl Me Me F H 3-Pyridyl A.12 nonafluorobut-2-yl Me Me F H 3-Pyridyl A.13 heptafluoroprop-2-yl H Et F H 3-Pyridyl A.14 nonafluorobut-2-yl H Et F H 3-Pyridyl A.15 heptafluoroprop-2-yl Me Et F H 3-Pyridyl A.16 nonafluorobut-2-yl Me Et F H 3-Pyridyl A.17 heptafluoroprop-2-yl H Me OCH₃ H 3-Pyridyl A.18 nonafluorobut-2-yl H Me OCH₃ H 3-Pyridyl A.19 heptafluoroprop-2-yl Me Me OCH₃ H 3-Pyridyl A.20 nonafluorobut-2-yl Me Me OCH₃ H 3-Pyridyl A.21 heptafluoroprop-2-yl H Et OCH₃ H 3-Pyridyl A.22 nonafluorobut-2-yl H Et OCH₃ H 3-Pyridyl A.23 heptafluoroprop-2-yl Me Et OCH₃ H 3-Pyridyl A.24 nonafluorobut-2-yl Me Et OCH₃ H 3-Pyridyl A.25 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me H H 4-Pyridyl A.26 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me H H 4-Pyridyl A.27 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me H H 4-Pyridyl A.28 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me H H 4-Pyridyl A.29 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et H H 4-Pyridyl A.30 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et H H 4-Pyridyl A.31 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et H H 4-Pyridyl A.32 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et H H 4-Pyridyl A.33 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H H H 4-Pyridyl A.34 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H H H 4-Pyridyl A.35 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H H H 4-Pyridyl A.36 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H H H 4-Pyridyl A.37 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me F H 4-Pyridyl A.38 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me F H 4-Pyridyl A.39 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me F H 4-Pyridyl A.40 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me F H 4-Pyridyl A.41 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et F H 4-Pyridyl A.42 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et F H 4-Pyridyl A.43 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et F H 4-Pyridyl A.44 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et F H 4-Pyridyl A.45 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H F H 4-Pyridyl A.46 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H F H 4-Pyridyl A.47 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H F H 4-Pyridyl A.48 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H F H 4-Pyridyl A.49 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me OCH₃ H 4-Pyridyl A.50 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Me OCH₃ H 4-Pyridyl A.51 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me OCH₃ H 4-Pyridyl A.52 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Me OCH₃ H 4-Pyridyl A.53 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et OCH₃ H 4-Pyridyl A.54 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H Et OCH₃ H 4-Pyridyl A.55 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et OCH₃ H 4-Pyridyl A.56 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me Et OCH₃ H 4-Pyridyl A.57 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H OCH₃ H 4-Pyridyl A.58 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl H H OCH₃ H 4-Pyridyl A.59 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H OCH₃ H 4-Pyridyl A.60 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl Me H OCH₃ H 4-Pyridyl A.61 heptafluoroprop-2-yl H Me H H 4-Pyridyl A.62 nonafluorobut-2-yl H Me H H 4-Pyridyl A.63 heptafluoroprop-2-yl Me Me H H 4-Pyridyl A.64 nonafluorobut-2-yl Me Me H H 4-Pyridyl A.65 heptafluoroprop-2-yl H Et H H 4-Pyridyl A.66 nonafluorobut-2-yl H Et H H 4-Pyridyl A.67 heptafluoroprop-2-yl Me Et H H 4-Pyridyl A.68 nonafluorobut-2-yl Me Et H H 4-Pyridyl A.69 heptafluoroprop-2-yl H H H H 4-Pyridyl A.70 nonafluorobut-2-yl H H H H 4-Pyridyl A.71 heptafluoroprop-2-yl Me H H H 4-Pyridyl A.72 nonafluorobut-2-yl Me H H H 4-Pyridyl A.73 heptafluoroprop-2-yl H Me F H 4-Pyridyl A.74 nonafluorobut-2-yl H Me F H 4-Pyridyl A.75 heptafluoroprop-2-yl Me Me F H 4-Pyridyl A.76 nonafluorobut-2-yl Me Me F H 4-Pyridyl A.77 heptafluoroprop-2-yl H Et F H 4-Pyridyl A.78 nonafluorobut-2-yl H Et F H 4-Pyridyl A.79 heptafluoroprop-2-yl Me Et F H 4-Pyridyl A.80 nonafluorobut-2-yl Me Et F H 4-Pyridyl A.81 heptafluoroprop-2-yl H H F H 4-Pyridyl A.82 nonafluorobut-2-yl H H F H 4-Pyridyl A.83 heptafluoroprop-2-yl Me H F H 4-Pyridyl A.84 nonafluorobut-2-yl Me H F H 4-Pyridyl A.85 heptafluoroprop-2-yl H Me OCH₃ H 4-Pyridyl A.86 nonafluorobut-2-yl H Me OCH₃ H 4-Pyridyl A.87 heptafluoroprop-2-yl Me Me OCH₃ H 4-Pyridyl A.88 nonafluorobut-2-yl Me Me OCH₃ H 4-Pyridyl A.89 heptafluoroprop-2-yl H Et OCH₃ H 4-Pyridyl A.90 nonafluorobut-2-yl H Et OCH₃ H 4-Pyridyl A.91 heptafluoroprop-2-yl Me Et OCH₃ H 4-Pyridyl A.92 nonafluorobut-2-yl Me Et OCH₃ H 4-Pyridyl A.93 heptafluoroprop-2-yl H H OCH₃ H 4-Pyridyl A.94 nonafluorobut-2-yl H H OCH₃ H 4-Pyridyl A.95 heptafluoroprop-2-yl Me H OCH₃ H 4-Pyridyl A.96 nonafluorobut-2-yl Me H OCH₃ H 4-Pyridyl A.97 heptafluoroprop-2-yl H Me H H 4-cyanophenyl A.98 nonafluorobut-2-yl H Me H H 4-cyanophenyl A.99 heptafluoroprop-2-yl Me Me H H 4-cyanophenyl A.100 nonafluorobut-2-yl Me Me H H 4-cyanophenyl A.101 heptafluoroprop-2-yl H Et H H 4-cyanophenyl A.102 nonafluorobut-2-yl H Et H H 4-cyanophenyl A.103 heptafluoroprop-2-yl Me Et H H 4-cyanophenyl A.104 nonafluorobut-2-yl Me Et H H 4-cyanophenyl A.105 heptafluoroprop-2-yl H Me F H 4-cyanophenyl A.106 nonafluorobut-2-yl H Me F H 4-cyanophenyl A.107 heptafluoroprop-2-yl Me Me F H 4-cyanophenyl A.108 nonafluorobut-2-yl Me Me F H 4-cyanophenyl A.109 heptafluoroprop-2-yl H Et F H 4-cyanophenyl A.110 nonafluorobut-2-yl H Et F H 4-cyanophenyl A.111 heptafluoroprop-2-yl Me Et F H 4-cyanophenyl A.112 nonafluorobut-2-yl Me Et F H 4-cyanophenyl A.113 heptafluoroprop-2-yl H Me OCH₃ H 4-cyanophenyl A.114 nonafluorobut-2-yl H Me OCH₃ H 4-cyanophenyl A.115 heptafluoroprop-2-yl Me Me OCH₃ H 4-cyanophenyl A.116 nonafluorobut-2-yl Me Me OCH₃ H 4-cyanophenyl A.117 heptafluoroprop-2-yl H Et OCH₃ H 4-cyanophenyl A.118 nonafluorobut-2-yl H Et OCH₃ H 4-cyanophenyl A.119 heptafluoroprop-2-yl Me Et OCH₃ H 4-cyanophenyl A.120 nonafluorobut-2-yl Me Et OCH₃ H 4-cyanophenyl A.121 heptafluoroprop-2-yl H Me H H 2-methyl-4-cyano-phenyl A.122 nonafluorobut-2-yl H Me H H 2-methyl-4-cyano-phenyl A.123 heptafluoroprop-2-yl Me Me H H 2-methyl-4-cyano-phenyl A.124 nonafluorobut-2-yl Me Me H H 2-methyl-4-cyano-phenyl A.125 heptafluoroprop-2-yl H Et H H 2-methyl-4-cyano-phenyl A.126 nonafluorobut-2-yl H Et H H 2-methyl-4-cyano-phenyl A.127 heptafluoroprop-2-yl Me Et H H 2-methyl-4-cyano-phenyl A.128 nonafluorobut-2-yl Me Et H H 2-methyl-4-cyano-phenyl A.129 heptafluoroprop-2-yl H Me F H 2-methyl-4-cyano-phenyl A.130 nonafluorobut-2-yl H Me F H 2-methyl-4-cyano-phenyl A.131 heptafluoroprop-2-yl Me Me F H 2-methyl-4-cyano-phenyl A.132 nonafluorobut-2-yl Me Me F H 2-methyl-4-cyano-phenyl A.133 heptafluoroprop-2-yl H Et F H 2-methyl-4-cyano-phenyl A.134 nonafluorobut-2-yl H Et F H 2-methyl-4-cyano-phenyl A.135 heptafluoroprop-2-yl Me Et F H 2-methyl-4-cyano-phenyl A.136 nonafluorobut-2-yl Me Et F H 2-methyl-4-cyano-phenyl A.137 heptafluoroprop-2-yl H Me OCH₃ H 2-methyl-4-cyano-phenyl A.138 nonafluorobut-2-yl H Me OCH₃ H 2-methyl-4-cyano-phenyl A.139 heptafluoroprop-2-yl Me Me OCH₃ H 2-methyl-4-cyano-phenyl A.140 nonafluorobut-2-yl Me Me OCH₃ H 2-methyl-4-cyano-phenyl A.141 heptafluoroprop-2-yl H Et OCH₃ H 2-methyl-4-cyano-phenyl A.142 nonafluorobut-2-yl H Et OCH₃ H 2-methyl-4-cyano-phenyl A.143 heptafluoroprop-2-yl Me Et OCH₃ H 2-methyl-4-cyano-phenyl A.144 nonafluorobut-2-yl Me Et OCH₃ H 2-methyl-4-cyano-phenyl A.145 heptafluoroprop-2-yl H Me H CN 2-methyl-4-cyano-phenyl A.146 nonafluorobut-2-yl H Me H CN 2-methyl-4-cyano-phenyl A.147 heptafluoroprop-2-yl Me Me H CN 2-methyl-4-cyano-phenyl A.148 nonafluorobut-2-yl Me Me H CN 2-methyl-4-cyano-phenyl A.149 heptafluoroprop-2-yl H Et H CN 2-methyl-4-cyano-phenyl A.150 nonafluorobut-2-yl H Et H CN 2-methyl-4-cyano-phenyl A.151 heptafluoroprop-2-yl Me Et H CN 2-methyl-4-cyano-phenyl A.152 nonafluorobut-2-yl Me Et H CN 2-methyl-4-cyano-phenyl A.153 heptafluoroprop-2-yl H H H CN 2-methyl-4-cyano-phenyl A.154 nonafluorobut-2-yl H H H CN 2-methyl-4-cyano-phenyl A.155 heptafluoroprop-2-yl Me H H CN 2-methyl-4-cyano-phenyl A.156 nonafluorobut-2-yl Me H H CN 2-methyl-4-cyano-phenyl

-   Table 1: Compounds of the formula (V) wherein X₁ is Cl, X₂ is Cl and     the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 2: Compounds of the formula (V) wherein X₁ is Br, X₂ is Cl and     the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 3: Compounds of the formula (V) wherein X₁ is I, X₂ is Cl and     the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 4: Compounds of the formula (V) wherein X₁ is methyl, X₂ is Cl     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 5: Compounds of the formula (V) wherein X₁ is ethyl, X₂ is Cl     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 6: Compounds of the formula (V) wherein X₁ is trifluoromethyl,     X₂ is Cl and the combination of the substituents X₃, R₁, R₂, R₃ and     Q₁ for each compound corresponds to a line A.1 to A.156 of Table A. -   Table 7: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is Cl and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 8: Compounds of the formula (V) wherein X₁ is difluoromethoxy,     X₂ is Cl and the combination of the substituents X₃, R₁, R₂, R₃ and     Q₁ for each compound corresponds to a line A.1 to A.156 of Table A. -   Table 9: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is Cl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 10: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is Cl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 11: Compounds of the formula (V) wherein X₁ is Br, X₂ is Br     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 12: Compounds of the formula (V) wherein X₁ is I, X₂ is Br and     the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 13: Compounds of the formula (V) wherein X₁ is methyl, X₂ is     Br and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 14: Compounds of the formula (V) wherein X₁ is ethyl, X₂ is Br     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 15: Compounds of the formula (V) wherein X₁ is     trifluoromethyl, X₂ is Br and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 16: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is Br and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 17: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is Br and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 18: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is Br and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 19: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is Br and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 20: Compounds of the formula (V) wherein X₁ is I, X₂ is I and     the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 21: Compounds of the formula (V) wherein X₁ is methyl, X₂ is I     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 22: Compounds of the formula (V) wherein X₁ is ethyl, X₂ is I     and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for     each compound corresponds to a line A.1 to A.156 of Table A. -   Table 23: Compounds of the formula (V) wherein X₁ is     trifluoromethyl, X₂ is I and the combination of the substituents X₃,     R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 24: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is I and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 25: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is I and the combination of the substituents X₃,     R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 26: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is I and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 27: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is I and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 28: Compounds of the formula (V) wherein X₁ is methyl, X₂ is     methyl and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁     for each compound corresponds to a line A.1 to A.156 of Table A. -   Table 29: Compounds of the formula (V) wherein X₁ is ethyl, X₂ is     methyl and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁     for each compound corresponds to a line A.1 to A.156 of Table A. -   Table 30: Compounds of the formula (V) wherein X₁ is     trifluoromethyl, X₂ is methyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 31: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is methyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 32: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is methyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 33: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is methyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 34: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is methyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 35: Compounds of the formula (V) wherein X₁ is ethyl, X₂ is     ethyl and the combination of the substituents X₃, R₁, R₂, R₃ and Q₁     for each compound corresponds to a line A.1 to A.156 of Table A. -   Table 36: Compounds of the formula (V) wherein X₁ is     trifluoromethyl, X₂ is ethyl and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line

A.1 to A.156 of Table A.

-   Table 37: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is ethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 38: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is ethyl and the combination of the substituents     X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to a line A.1 to     A.156 of Table A. -   Table 39: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is ethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 40: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is ethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 41: Compounds of the formula (V) wherein X₁ is     trifluoromethyl, X₂ is trifluoromethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 42: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is trifluoromethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 43: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is trifluoromethyl and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 44: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is trifluoromethyl and the combination of     the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds     to a line A.1 to A.156 of Table A. -   Table 45: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is trifluoromethyl and the combination     of the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound     corresponds to a line A.1 to A.156 of Table A. -   Table 46: Compounds of the formula (V) wherein X₁ is     trifluoromethoxy, X₂ is trifluoromethoxy and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 47: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is trifluoromethoxy and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 48: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is trifluoromethoxy and the combination of     the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds     to a line A.1 to A.156 of Table A. -   Table 49: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is trifluoromethoxy and the combination     of the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound     corresponds to a line A.1 to A.156 of Table A. -   Table 50: Compounds of the formula (V) wherein X₁ is     difluoromethoxy, X₂ is difluoromethoxy and the combination of the     substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds to     a line A.1 to A.156 of Table A. -   Table 51: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is difluoromethoxy and the combination of     the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound corresponds     to a line A.1 to A.156 of Table A. -   Table 52: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is difluoromethoxy and the combination     of the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound     corresponds to a line A.1 to A.156 of Table A. -   Table 53: Compounds of the formula (V) wherein X₁ is     trifluoromethylthio, X₂ is trifluoromethylthio and the combination     of the substituents X₃, R₁, R₂, R₃ and Q₁ for each compound     corresponds to a line A.1 to A.156 of Table A. -   Table 54: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is trifluoromethylthio and the     combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A. -   Table 55: Compounds of the formula (V) wherein X₁ is     trifluoromethylsulfinyl, X₂ is trifluoromethylsulfinyl and the     combination of the substituents X₃, R₁, R₂, R₃ and Q₁ for each     compound corresponds to a line A.1 to A.156 of Table A.

TABLE B (IV)

Line n° R₂ R₃ R_(3a) Q₁ B.1  Me H H 3-Pyridyl B.2  Et H H 3-Pyridyl B.3  Me F H 3-Pyridyl B.4  Et F H 3-Pyridyl B.5  Me OCH₃ H 3-Pyridyl B.6  Et OCH₃ H 3-Pyridyl B.7  Me H H 4-Pyridyl B.8  Et H H 4-Pyridyl B.9  Me F H 4-Pyridyl B.10 Et F H 4-Pyridyl B.11 Me OCH₃ H 4-Pyridyl B.12 Et OCH₃ H 4-Pyridyl B.13 Me H H 2-methyl-4-cyano-phenyl B.14 Et H H 2-methyl-4-cyano-phenyl B.15 Me F H 2-methyl-4-cyano-phenyl B.16 Et F H 2-methyl-4-cyano-phenyl B.17 Me OCH₃ H 2-methyl-4-cyano-phenyl B.18 Et OCH₃ H 2-methyl-4-cyano-phenyl B.19 Me H CN 2-methyl-4-cyano-phenyl B.20 Et H CN 2-methyl-4-cyano-phenyl

-   Table 56: Compounds of the formula (IV) wherein X₄ is Cl and the     combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 57: Compounds of the formula (IV) wherein X₄ is F and the     combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 58: Compounds of the formula (IV) wherein X₄ is Br and the     combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 59: Compounds of the formula (IV) wherein X₄ is I and the     combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 60: Compounds of the formula (IV) wherein X₄ is acetoxy and     the combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 61: Compounds of the formula (IV) wherein X₄ is formyloxy and     the combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 62: Compounds of the formula (IV) wherein X₄ is benzoyloxy and     the combination of the substituents R₂, R₃ and Q₁ for each compound     corresponds to a line B.1 to B.20 of Table B. -   Table 63: Compounds of the formula (IV) wherein X₄ is     methoxycarbonyloxy and the combination of the substituents R₂, R₃     and Q₁ for each compound corresponds to a line B.1 to B.20 of Table     B. -   Table 64: Compounds of the formula (IV) wherein X₄ is     ethoxycarbonyloxy and the combination of the substituents R₂, R₃ and     Q₁ for each compound corresponds to a line B.1 to B.20 of Table B. -   Table 65: Compounds of the formula (IV) wherein X₄ is     isopropoxycarbonyloxy and the combination of the substituents R₂, R₃     and Q₁ for each compound corresponds to a line B.1 to B.20 of Table     B. -   Table 66: Compounds of the formula (IV) wherein X₄ is     phenoxycarbonyloxy and the combination of the substituents R₂, R₃     and Q₁ for each compound corresponds to a line B.1 to B.20 of Table     B. -   Table 67: Compounds of the formula (IV) wherein X₄ is     benzyloxycarbonyloxy and the combination of the substituents R₂, R₃     and Q₁ for each compound corresponds to a line B.1 to B.20 of Table     B. -   Table 68: Compounds of the formula (IV) wherein X₄ is imidazol-1-yl     and the combination of the substituents R₂, R₃ and Q₁ for each     compound corresponds to a line B.1 to B.20 of Table B.

TABLE C (III) (IIIa)

Line n° X₁ X₂ C.1  Cl Cl C.2  Br Cl C.3  I Cl C.4  Me Cl C.5  Et Cl C.6  CF₃ Cl C.7  OCF₃ Cl C.8  OCHF₂ Cl C.9  SCF₃ Cl C.10 S(O)CF₃ Cl C.11 Br Br C.12 I Br C.13 Me Br C.14 Et Br C.15 CF₃ Br C.16 OCF₃ Br C.17 OCHF₂ Br C.18 SCF₃ Br C.19 S(O)CF₃ Br C.20 I I C.21 Me I C.22 Et I C.23 CF₃ I C.24 OCF₃ I C.25 OCHF₂ I C.26 SCF₃ I C.27 S(O)CF₃ I C.28 Me Me C.29 Et Me C.30 CF₃ Me C.31 OCF₃ Me C.32 OCHF₂ Me C.33 SCF₃ Me C.34 S(O)CF₃ Me C.35 Et Et C.36 CF₃ Et C.37 OCF₃ Et C.38 OCHF₂ Et C.39 SCF₃ Et C.40 S(O)CF₃ Et C.41 CF₃ CF₃ C.42 OCF₃ CF₃ C.43 OCHF₂ CF₃ C.44 SCF₃ CF₃ C.45 S(O)CF₃ CF₃ C.46 OCF₃ OCF₃ C.47 OCHF₂ OCF₃ C.48 SCF₃ OCF₃ C.49 S(O)CF₃ OCF₃ C.50 OCHF₂ OCHF₂ C.51 SCF₃ OCHF₂ C.52 S(O)CF₃ OCHF₂ C.53 SCF₃ SCF₃ C.54 S(O)CF₃ SCF₃ C.55 S(O)CF₃ S(O)CF₃

-   Table 69: Compounds of the formula (III) wherein X₃ is     heptafluoroprop-2-yl, R₁ is H and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 70: Compounds of the formula (III) wherein X₃ is     heptafluoroprop-2-yl, R₁ is methyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 71: Compounds of the formula (III) wherein X₃ is     heptafluoroprop-2-yl, R₁ is ethyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 72: Compounds of the formula (III) wherein X₃ is     heptafluoroprop-2-yl, R₁ is isopropyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 73: Compounds of the formula (III) wherein X₃ is     nonafluorobut-2-yl, R₁ is H and the combination of the substituents     X₁ and X₂ for each compound corresponds to a line C.1 to C.55 of     Table C. -   Table 74: Compounds of the formula (III) wherein X₃ is     nonafluorobut-2-yl, R₁ is methyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 75: Compounds of the formula (III) wherein X₃ is     nonafluorobut-2-yl, R₁ is ethyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 76: Compounds of the formula (III) wherein X₃ is     nonafluorobut-2-yl, R₁ is isopropyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 77: Compounds of the formula (IIIa) wherein X₃ is     heptafluoroprop-2-yl, R₁ is H and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 78: Compounds of the formula (IIIa) wherein X₃ is     heptafluoroprop-2-yl, R₁ is methyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 79: Compounds of the formula (IIIa) wherein X₃ is     heptafluoroprop-2-yl, R₁ is ethyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 80: Compounds of the formula (IIIa) wherein X₃ is     heptafluoroprop-2-yl, R₁ is isopropyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 81: Compounds of the formula (IIIa) wherein X₃ is     nonafluorobut-2-yl, R₁ is H and the combination of the substituents     X₁ and X₂ for each compound corresponds to a line C.1 to C.55 of     Table C. -   Table 82: Compounds of the formula (IIIa) wherein X₃ is     nonafluorobut-2-yl, R₁ is methyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 83: Compounds of the formula (IIIa) wherein X₃ is     nonafluorobut-2-yl, R₁ is ethyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 84: Compounds of the formula (IIIa) wherein X₃ is     nonafluorobut-2-yl, R₁ is isopropyl and the combination of the     substituents X₁ and X₂ for each compound corresponds to a line C.1     to C.55 of Table C. -   Table 85: Compounds of the formula (III) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is H and     the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 86: Compounds of the formula (III) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is methyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 87: Compounds of the formula (III) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is ethyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 88: Compounds of the formula (III) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is     isopropyl and the combination of the substituents X₁ and X₂ for each     compound corresponds to a line C.1 to C.55 of Table C. -   Table 89: Compounds of the formula (III) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is H and the     combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 90: Compounds of the formula (III) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is methyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 91: Compounds of the formula (III) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is ethyl and     the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 92: Compounds of the formula (III) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is isopropyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 93: Compounds of the formula (IIIa) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is H and     the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 94: Compounds of the formula (IIIa) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is methyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 95: Compounds of the formula (IIIa) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is ethyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 96: Compounds of the formula (IIIa) wherein X₃ is     1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is     isopropyl and the combination of the substituents X₁ and X₂ for each     compound corresponds to a line C.1 to C.55 of Table C. -   Table 97: Compounds of the formula (IIIa) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is H and the     combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 98: Compounds of the formula (IIIa) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is methyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 99: Compounds of the formula (IIIa) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is ethyl and     the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C. -   Table 100: Compounds of the formula (IIIa) wherein X₃ is     1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, R₁ is isopropyl     and the combination of the substituents X₁ and X₂ for each compound     corresponds to a line C.1 to C.55 of Table C.

PREPARATION EXAMPLES Examples

The following abbreviations were used throughout this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point.

Example 1 Methyl 3-(ethylamino)-2-methoxy-benzoate

A pressure vial was charged with Pd/C (10%, 0.021 g) and 2-propanol (3.4 ml). A solution of ammonium formiate (0.452 g, 7.10 mmol) in water (0.35 ml) was added and the resulting mixture was stirred for 5 min. Methyl 2-methoxy-3-nitro-benzoate (0.100 g, 0.473 mmol) was added and the reaction media was cooled to 0 C. Acetaldehyde (0.105 g, 2.37 mmol) was added and the reaction media was stirred for 16 h at ambient temperature. The reaction mixture was filtered through a short pad of celite and filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with brine. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-30% EtOAc in cyclohexane) to give methyl 3-(ethylamino)-2-methoxy-benzoate (0.0839 g, 85%) as a beige oil. ¹H NMR (400 MHz, CDCl₃): 7.09 (dd, 1H), 7.01 (t, 1H), 6.77 (dd, 1H), 4.30 (bs, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.16 (q, 2H), 1.27 (t, 3H) ppm.

Example 2 Methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate

To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (0.158 g, 0.754 mmol) in dichloromethane (2.6 ml) was added triethylamine (0.233 ml, 1.66 mmol) followed by 4-cyanobenzoyl chloride (0.140 g, 0.829 mmol). After stirring at ambient temperature for 16 h the reaction was quenched by addition of saturated aqueous NH₄Cl. The mixture was extracted with dichloromethane (2x) and organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-40% EtOAc in cyclohexane) to give methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate (0.207 g, 81%) as a beige gum.

¹H NMR (400 MHz, CDCl₃): 7.77-7.58 (m, 1H), 7.55-7.35 (m, 4H), 7.32-7.20 (m, 1H), 7.12-6.99 (m, 1H), 4.20 (bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73-3.61 (m, 1H), 1.33-1.21 (m, 3H) ppm

Example 3 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid

To a solution of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate (0.120 g, 0.354 mmol) in MeOH (1.2 ml) was added 5M NaOH (0.142 ml, 0.707 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature before being quenched by addition of aqueous saturated NH₄Cl. The mixture was extracted with dichloromethane (3x), combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid (0.0827 g, 72%) as a white solid sufficiently pure for further chemistry.

¹H NMR (400 MHz, CDCl₃): 7.98-7.78 (m, 1H), 7.68-7.29 (m, 5H), 7.25-7.10 (m, 1H), 4.30 (bs, 1H), 3.91 (s, 3H), 3.71-3.57 (m, 1H), 1.42-1.19 (m, 3H) ppm

Example 4 N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

A solution of 2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (5.00 g, 12.0 mmol) in acetic anhydride (30 ml) was heated to 60 C and few drops of concentrated sulfuric acid was added. The heating was continued for further 90 min and then most of acetic anhydride was evaporated under reduced pressure. The residue was taken dissolved in THF (25 ml) and aqueous 2N NaOH (35 ml) was added. The reaction mixture was stirred at ambient temperature for 2 h before being extracted with dichloromethane (3x). Combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-40% EtOAc in cyclohexane) to afford N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (5.00 g, 90%) as a beige solid.

¹H NMR (400 MHz, CDCl₃): 7.77 (s, 1H), 7.66 (s, 1H), 7.18 (brs, 1H), 2.24 (brs, 3H) ppm.

Example 5 N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide Step 1

Preparation of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoyl chloride. To a suspension of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid (1.00 g, 3.08 mmol) in 1,2-dichloroethane was one drop of DMF followed by a slow addition of oxalyl chloride (0.284 ml, 3.24 mmol). The reaction mixture was stirred for further 30 min to afford a solution of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoyl chloride which was used for the next step immediately.

Step 2

To a solution of N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (1.28 g, 3.08 mmol) in 1,2-dichlorethane (11 ml) was added triethylamine (1.08 ml, 7.70 mmol). The solution of acid chloride prepared in the step 1 was added dropwise at 0 C and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by addition of aqueous saturated NaHCO3, the aqueous phase was extracted with DCM (3x), the combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-30% EtOAc in cyclohexane) to afford N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (1.61 g, 71%) as a white solid.

¹H NMR (400 MHz, CDCl₃): 7.88 (brs, 1H), 7.81-7.73 (m, 1H), 7.56-7.41 (m, 4H), 7.39-7.31 (m, 1H), 7.17-7.07 (m, 1H), 7.04-6.94 (m, 1H), 4.34-4.19 (m, 1H), 3.90 (s, 3H), 3.73-3.59 (m, 1H), 2.02-1.87 (m, 3H), 1.36-1.22 (m, 3H) ppm.

Example 6 N-[2-bromo-6-chloro-4-[1,1,1,2,3,3,3-heptafluoro-prop-2-yl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide

To a solution of N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (0.0750 g, 0.0995 mmol) in THF (0.5 ml) was added 1N NaOH (0.40 ml, 0.40 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford pure N-[2-bromo-6-chloro-4-[1,1,1,2,3,3,3-heptafluoro-prop-2-yl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (0.0706 g, 98%) as a beige solid.

¹H NMR (400 MHz, CDCl₃): 8.78 (bs, 1H), 8.04 (d, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.55 (d, 1H), 7.40-7.55 (m, 4H), 7.43 (t, 1H), 4.34-4.48 (m, 1H), 3.96 (s, 3H), 3.67-3.80 (m, 1H), 1.48 (t, 3H) ppm.

Example 7 methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate

To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (1.168 g, 5.58 mmol) in DCM (20 ml) was added triethylamine (1.89 ml, 13.40 mmol) followed by isonicotinoyl chloride hydrochloride (1.217 g, 6.70 mmol) and the reaction mixture was stirred at 40 C for 1 h. The reaction mixture was cooled to room temperature and quenched by addition of aqueous saturated NaHCO₃ and 1N NaOH was added until pH=8-9. The aqueous phase was extracted with DCM (3x), combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (1.644 g, 94%) as a beige oil.

¹H NMR (400 MHz, CDCl₃): 8.44 (s, 2H), 7.65 (d, 1H), 7.30-7.11 (m, 3H), 7.09-6.98 (m, 1H), 4.31-4.17 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.71-3.59 (m, 1H), 1.33-1.23 (m, 3H) ppm.

Example 8 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride

To a solution of methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (0.108 g, 0.343 mmol) in a mixture of THF (0.82 ml) and water (0.28 ml) was added lithium hydroxide hydrate (0.0153 g, 0.36 mmol). The reaction mixture was stirred at 50 C for 1 h, cooled to room temperature and acidified with 1N HCl. The reaction mixture was extracted with DCM (3x), the combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. Thus obtained crude 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride (0.060 g, 52%) was without further purification.

¹H NMR (400 MHz, CDCl₃): 8.48 (s, 2H), 7.89 (d, 1H), 7.43-7.32 (m, 1H), 7.27-7.09 (m, 3H), 4.38-4.24 (m, 1H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 1.40-1.27 (m, 3H) ppm.

Example 9 N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide Step 1

Preparation of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoyl chloride hydrochloride. To a suspension of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride (0.0985 g, 0.278 mmol) in 1,2-dichloroethane (0.83 ml) was added one drop of DMF followed by slow addition of oxalyl chloride (0.0256 ml, 0.292 mmol). The resulting reaction mixture was stirred at room temperature for 40 min to afford a solution of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoyl chloride hydrochloride which was immediately used for the next step.

Step 2

To a solution of N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (0.116 g, 0.278 mmol) in 1,2-dichloroethane (0.83 ml) was added triethylamine (0.137 ml, 0.973 mmol) followed by a dropwise addition of the solution of acid chloride prepared in the step 1 at 0 C. The resulting reaction mixture was stirred at room temperature for 2 h and quenched by addition of aqueous saturated NaHCO₃. The aqueous phase was extracted with DCM (3x), combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.116 g, 59%) as a white solid.

¹H NMR (400 MHz, CDCl₃): 8.56-8.41 (m, 2H), 7.87 (s, 1H), 7.75 (d, 1H), 7.44-7.32 (m, 1H), 7.26-7.08 (m, 3H), 7.05-6.93 (m, 1H), 4.34-4.20 (m, 1H), 3.91 (s, 3H), 3.71-3.58 (m, 1H), 2.67 (d, 3H), 1.35-1.21 (m, 3H) ppm.

Example 10 N-[3-[[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide

To a solution of N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.106 g, 0.152 mmol) in THF (0.76 ml) was added 1M NaOH (0.61 ml, 0.61 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (3x). Combined organic layers were dried over anhydrous Na₂SO₄ and evaporated under reduced pressure to afford a pure N-[3-[[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.100 g, 96%) as a white solid.

¹H NMR (400 MHz, CDCl₃): 8.79 (s, 1H), 8.47 (s, 2H), 8.06 (d, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.53-7.47 (m, 1H), 7.35-7.27 (m, 1H), 7.23-7.13 (m, 2H), 4.46-4.33 (m, 1H), 3.96 (s, 3H), 3.76-3.64 (m, 1H), 1.48-1.38 (m, 3H) ppm.

Example 11 N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)phenyl]acetamide

From 200 mg 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)phenyl]acetamide was obtained (104 mg, 47%).

¹H NMR (400 MHz, CDCl₃): 7.77 (s, 1H), 7.48 (s, 1H), 6.93 (brs, 1H), 6.52 (t, 1H), 2.26 (s, 3H) ppm.

Example 12 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline

2.41 g N-bromosuccinimide was slowly added to a solution of 3.88 g 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline (Example 13) in 24 ml Dichloromethane at ambient temperature. A slightly exothermic reaction was observed. The mixture was stirred for 1 hour at ambient temperature. Then 100 ml of aqueous sodium hydroxide (1N) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (1N). The aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline (4.58 g, 96%) was obtained as a dark brown oil.

¹H NMR (400 MHz, CDCl₃): 7.55 (s, 1H), 7.24 (s, 1H), 6.50 (t, 1H), 4.60 (brs, 2H) ppm.

Example 13 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline

6.8 g Sodium hydrosulphite, 2.8 g sodium bicarbonate, 0.69 g tetrabutylammonium hydrogensulphate and 10 g 1-chloro-1,1,2,3,3,3-hexafluoro-2-iodo-propane were added to a solution of 4.5 g 2-(difluoromethoxy)aniline in a mixture of 41 ml 2-methoxy-2-methyl-propane and 41 ml water. The reaction mixture was stirred for 3 days at ambient temperature. Then the layers were separated, the aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (1N), twice with 100 ml portions of water, once with 100 ml of brine, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline (3.88 g, 41%) was obtained as an orange oil.

¹H NMR (400 MHz, CDCl₃): 7.28 (m, 2H), 6.82 (d, 1H), 6.49 (t, 1H), 4.12 (brs, 2H) ppm.

Example 14 N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide

From 200 mg 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (151 mg, 68%).

¹H NMR (400 MHz, CDCl₃): 7.51 (s, 1H), 7.74 (s, 1H), 6.91 (brs, 1H), 2.71 (q, 2H), 2.25 (s, 3H), 1.23 (t, 3H) ppm.

Example 15 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline

6.67 g N-bromosuccinimide was slowly added to a solution of 9.54 g 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline in 67 ml dichloromethane at ambient temperature. An exothermic reaction was observed. The mixture was stirred for 1.5 hours at ambient temperature. Then 100 ml of aqueous sodium hydroxide (1N) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (1N). The combined aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline (12.0 g, 100%) was obtained as a dark brown oil.

¹H NMR (400 MHz, CDCl₃): 7.53 (s, 1H), 7.20 (s, 1H), 4.38 (brs, 2H), 2.56 (q, 2H), 1.27 (t, 3H) ppm.

Example 16 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline

9.66 Sodium hydrosulphite, 3.96 g sodium bicarbonate, 0.97 g tetrabutylammonium hydrogensulphate and 13.5 g 1-chloro-1,1,2,3,3,3-hexafluoro-2-iodo-propane were added to a solution of 4.86 g 2-ethylaniline in a mixture of 58 ml 2-methoxy-2-methyl-propane and 58 ml water. The reaction mixture was stirred 2 hours at ambient temperature. Then the layers were separated. The aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (1N), twice with 100 ml portions of water, once with 100 ml brine, dried over sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline (9.54 g, 79%) was obtained as an orange oil.

¹H NMR (400 MHz, CDCl₃): 7.26 (m, 2H), 6.70 (d, 1H), 3.85 (brs, 2H), 2.53 (q, 2H), 1.27 (t, 3H) ppm.

Example 17 N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.98 g, 89%).

¹H NMR (400 MHz, CDCl₃): 7.82 (s, 2H), 7.00 (brs, 1H), 2.26 (brs, 3H) ppm.

Example 18 N-[2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.93 g, 82%).

¹H NMR (400 MHz, CDCl₃): 7.33 (s, 2H), 6.70 (brs, 1H), 2.63 (q, 4H), 2.24 (s, 3H), 1.20 (t, 6H) ppm.

Example 19 N-[2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 323 mg 2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (232 mg, 64%).

¹H NMR (400 MHz, CDCl₃): 7.60 (s, 1H), 7.41 (s, 1H), 6.92 (brs, 1H), 6.53 (t, 1H), 2.24 (s, 3H) ppm.

Example 20 N-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.296 g, 26%).

¹H NMR (400 MHz, CDCl₃): 7.62 (s, 2H), 6.95 (brs, 1H), 2.25 (brs, 3H) ppm.

Example 21 N-[2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (1.038 g, 91%).

¹H NMR (400 MHz, CDCl₃): 7.52 (s, 1H), 7.39 (s, 1H), 6.96 ppm (brs, 1H), 2.37 (s, 3H), 2.26 (s, 3H) ppm.

Example 22 N-[2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (1.1 g, 97%).

¹H NMR (400 MHz, CDCl₃): 7.54 (s, 1H), 7.42 (s, 1H), 6.88 (brs, 1H), 2.70 (q, 2H), 2.27 (s, 3H), 1.23 (t, 3H) ppm.

Example 23 2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline

27.9 g 1-chloropyrrolidine-2,5-dione was added in portions to a solution of 60.5 g 2-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline in 350 ml dichloromethane. The reaction mixture was stirred for 3 days at ambient temperature. Then, 150 ml of aqueous sodium hydroxide (1N) were slowly added, during addition an exothermic reaction was observed. The layers were separated and the organic layer was washed twice with 100 ml of aqueous sodium hydroxide (1N), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue, 64.2 g of a dark brown powder, was purified by flash chromatography using dichloromethane/cyclohexane as a solvent. Thus, 2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (50.2 g, 74%) was obtained as a pale orange solid.

¹H NMR (400 MHz, CDCl₃): 7.88 (s, 1H), 7.17 (s, 1H), 4.33 brs, 2H), 2.56 (q, 2H), 1.28 (t, 3H) ppm.

Example 24 N-[2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (098 g, 88%).

¹H NMR (400 MHz, CDCl₃): 7.70 (s, 1H), 7.45 (s, 1H), 6.87 (brs, 1H), 2.41 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm.

Example 25 N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

From 1.0 g 2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (954 mg, 86%).

¹H NMR (400 MHz, CDCl₃): 7.75 (s, 1H), 7.46 (s, 1H), 6.95 (brs, 1H), 6.52 (t, 1H), 2.24 (s, 3H) ppm.

Example 26 N-[2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide

From 500 mg 2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (520 mg, 95%).

¹H NMR (400 MHz, CDCl₃): 7.70 (s, 1H), 7.48 (s, 1H), 7.01 (brs, 1H), 2.70 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm.

Example 27 N-[2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]phenyl]acetamide

From 500 mg 2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]phenyl]acetamide was obtained (340 mg, 71%).

¹H NMR (400 MHz, CDCl₃): 7.84 (s, 2H), 7.01 (brs, 1H), 2.28 (s, 3H) ppm.

Example 28 N-[4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-phenyl]acetamide

From 500 mg 4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-aniline, following the same procedure as described in Example 4, N-[4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-phenyl]acetamide was obtained (320 mg, 72%).

¹H NMR (400 MHz, CDCl₃): 7.64 (s, 2H), 6.95 (brs, 1H), 2.27 (s, 3H) ppm.

Example 29 N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide

From 760 mg N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide and 520 mg 2-methoxy-3-[methyl(pyridine-4-carbonyl)amino]benzoyl chloride, following the same procedure as described in Example 5, Step 2, N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide was obtained (446 mg, 37%).

¹H NMR (400 MHz, CDCl₃): 8.50 (brs, 2H), 7.77 (m, 1H), 7.43 (brs, 1H), 7.20-7.30 (m, broad, 4H), 7.05 (m, 1H), 6.45 (t, broad, 1H), 3.88 (s, 3H), 3.43 (brs, 3H), 1.96 (brs, 3H) ppm.

Example 30 N-[3-[[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide

From 278 g N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide, following the same procedure as described in Example 6, N-[3-[[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide was obtained (259 mg, 99%).

¹H NMR (400 MHz, CDCl₃): 8.73 (brs, 1H), 8.47 (brs, 2H), 8.03 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.45 (s, 1H), 7.35 (t, 1H), 7.17 (brs, 2H), 6.53 (t, 1H), 3.62 (brs, 3H), 3.58 (brs, 3H) ppm. 

1. A method for the preparation of

comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of acid to obtain a compound of formula (III):

then Step b) reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V):

then Step c) reacting the compound of formula (V) with aqueous base to obtain a compound of formula (VI):

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl; R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, R₂ is C₁-C₄-alkyl R₃ is H, fluorine, methoxy; R_(3a) is H or CN, Q₁ is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;
 2. A compound according to formula (III)

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,
 3. A compound according to formula (IV)

wherein X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—, phenoxy-C(O)O—, benzyloxy-C(O)O— and imidazol-1-yl; R₂ is C₁-C₄-alkyl; R₃ is H, fluorine, methoxy; R_(3a) is H or CN; Q₁ is 3-pyridyl or 4-pyridyl; provided that not both R₃ and R_(3a) are H; or a compound according to formula (V)

wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, C₁-C₄-alkylsulphonyl, C₁-C₄-haloalkylsulphonyl, C₁-C₄-alkylsulphinyl, C₁-C₄-haloalkylsulphinyl, C₁-C₄-alkylthio, C₁-C₄-haloalkylthio, X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; R₁ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, R₂ is C₁-C₄-alkyl R₃ is H, fluorine, methoxy, R_(3a) is H or CN, Q₁ is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;
 4. (canceled)
 5. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, X₃ is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—; R₁ is H, C₁-C₄ alkyl, R₂ is methyl or ethyl Q₁ is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl;
 6. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkoxymethyl, X₃ is 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—, phenyl-C(O)O—, C₁-C₆-alkoxy-C(O)O—; R₁ is H, C₁-C₄ alkyl, R₂ is methyl or ethyl Q₁ is 3-pyridyl or 4-pyridyl;
 7. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, X₃ is heptafluoroprop-2-yl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—; R₁ is H, methyl, R₂ is ethyl Q₁ is 4-pyridyl;
 8. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, X₃ is heptafluoroprop-2-yl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—; R₁ is H, methyl, R₂ is ethyl Q₁ is 4-pyridyl;
 9. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, X₃ is 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—; R₁ is H, methyl, R₂ is ethyl Q₁ is 4-pyridyl;
 10. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, X₃ is 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—; R₁ is H, methyl, R₂ is ethyl Q₁ is 4-pyridyl;
 11. A method according to claim 1 wherein X₁ and X₂ each independently are halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, X₃ is nonafluorobut-2-yl; X₄ is a leaving group selected from halogen, C₁-C₆-alkyl-C(O)O—; R₁ is H, methyl, R₂ is ethyl Q₁ is 4-pyridyl;
 12. A method according to claim 1 wherein R₃ is methoxy and R_(3a) is H,
 13. A method according to claim 1 wherein R₃ is fluorine and R_(3a) is H,
 14. A method according to claim 1 wherein R₃ is H and R_(3a) is CN,
 15. A method according to claim 1 wherein R₃ is H and R_(3a) is H. 